1. Field of the Invention
The present invention relates to a calcium phosphate-based excipient that can be used in making formulations, and to processes of making and using the same.
2. Description of the Prior Art
Solid dosage forms are a convenient way to deliver active agents. Tablets and capsules are common types of solid dosage forms. Generally tablets are made by compressing a solid material, which contains an active substance, in a tablet press. For efficiency and quality reasons in manufacturing, the material is desired to exhibit certain physical characteristics. For example, the material should be free-flowing (to insure that the space of the die cavity in the press is uniformly filled), should not be adhesive to the tablet punch surface (to be readily ejected from the punch faces) and possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression. Since most of the active ingredients, particularly most of the pharmaceutically active ingredients, do not have all of these properties, inactive ingredients, i.e., “excipients,” are frequently added to the active ingredient in order to impart desirable characteristics. Additionally, excipients known as fillers or solid diluents are sometimes added to increase the bulk weight of the material to be tabletted to a more practical size for compression/tabletting.
Furthermore, other kinds of excipients may be added to the tabletting material for reasons other than manufacturing, e.g. to allow the tablet to disintegrate after administration, to modify the release of the active agent from the tablet, to stabilize the active agent, to protect the tablet composition against moisture, etc. Some excipients have more than one effect. For instance, microcrystalline cellulose is an excipient that has good binding properties and provides good disintegration properties.
Several general schemes are available for combining the active agent and excipient(s) to form the tablettable material. In one scheme, the active agent is granulated with one or more excipients into free flowing granules, which are then mixed/homogenized with the remaining solid excipients, if any, and the resulting free flowing mixture is then tabletted. There are three general and well known methods for performing the granulation: wet granulation, dry granulation and hot-melt granulation. Granulation is also often used to provide a modulated release of the active from the tablet composition due to both the physical effect of granulation as well the kind of excipients used in modifying release rate.
A simpler and more modem tabletting process however involves the direct compression of a solid mixture of the active agent and excipients into a tablet, without granulating or modifying the active agent. While this direct compression process is the simplest and cheapest, it also has its limitations. For instance, only a limited number of excipients are suitable for this process; i.e., excipients with excellent binding properties, good flow and high compressibility. Direct tabletting excipients should also have a high uptake capacity for the active agent in that active agents are frequently difficult to compress. Further, the excipient should not have too high a density or else segregation of the different parts of the material to be compressed can occur. Optimally, the resulting tablets are generally intended to have low friability and high fracture resistance.
Some of these requirements are contradictory. For example, high tablet fracture resistance is associated with a large area of contact between the active agent and the diluent/binder inside the tablet. This can be achieved by the use of diluent and binder in the form of fine particles. However, fine-particles tend to have poor flow properties which limits their suitability in high speed processes.
Direct compression is also limited in making a modified release dosage form, i.e. a non-immediate release tablet. In general, there are only a limited number of suitable excipients for making controlled release dosage forms by direct compression tabletting. An example of such a suitable excipient is hydroxypropylmethylcellulose (HPMC).
In addition to making tablets, active agents can be formulated into other solid dosage forms such as capsules. A capsule generally contains the active material encapsulated such as by a hard or soft gelatin capsule. The active material is again normally combined with excipients for bulk, handling, etc., reasons. A common process for forming a capsule dosage form involves granulating the active agent with one or more excipients, optionally coating the granulates, and filling the capsule with the granulate. This is especially useful for modified release dosage forms. Indeed, a mixture of granules having different release characteristics, e.g. immediate, moderate and delayed, can be filled into a capsule to provide an overall sustained release profile.
One common excipient is calcium phosphate in one of several forms, e.g., monobasic, dibasic, and tribasic in anhydrous or hydrated form. Calcium phosphate is considered to be suitable for both granulation and direct compression tabletting processes because of its compaction properties, good binding properties and good flow properties of the coarse-grade material. However, calcium phosphate has certain disadvantageous properties. For instance, calcium phosphates are abrasive and at higher pressures the tablet can exhibit lamination and capping. This phenomenon can be observed when the calcium phosphate comprises a substantial proportion of the formulation and is exacerbated by the use of deep concave tooling. Further, calcium phosphate can be incompatible with some active agents, such as pH-sensitive pharmaceutical active agents. The surface of milled anhydrous dibasic calcium phosphate is alkaline and consequently it is generally not used with active agents that are sensitive to alkaline pH. On the other hand, the coarse grade form has an acidic surface environment. Beyond this, the overall pH of the calcium phosphate can vary by brand from acidic to alkaline. The pH can have important implications for stability of the dosage form.
Another limitation of calcium phosphate is its inability to provide a controlled/modified release rate. Generally an additional excipient having release modulation properties must be incorporated into the dosage form, such as in the tablet matrix or as a coating thereon.
Another excipient is a wax. Waxes are hydrophobic compounds, many of which are known for use in oral solid dosage pharmaceutical formulations as lubricants or as a sustained-release matrix (for example, see EP 665010). In general, the release rate decreases with increasing wax content, but at the same time compression properties are worsened with increasing wax content. Waxes generally have poor flow properties, which makes them less suitable or, particularly at higher contents necessary to produce controlled-release profiles, unsuitable for direct compression. Instead, these hydrophobic substances usually have to be pre-treated with the active agent when used to make a controlled release dosage form. Some of the more common fatty acid waxes have typically been used as follows:
Glyceryl Behenate is used as tablet and capsule lubricant: 0.5-5%, and as matrix for sustained release: 10-30%.
Glyceryl Palmitostearate is used as tablet and capsule lubricant: 0.5-5%, and as matrix for sustained release: 10-50%.
Hydrogenated Castor Oil is used as tablet and capsule lubricant: 0.1-2%, and as matrix for sustained release: 5-10%.
Glyceryl behenate and glyceryl palmitostearate are each available in grades that can be used for direct compression (e.g. COMPRITOL ATO 888 from Gattefossé and PRECIROL ATO 5 from Gattefossé, respectively), but usually the compositions including them are prepared by pre-granulation of the wax with the active agent and other excipients before compression because of poor flowing properties of the wax itself
Attempts have been made over the years to improve or modify excipients so that their unsuitable properties are substantially eliminated while retaining the beneficial characteristics. Some of these approaches involve combining two or more excipients into a singular multicomponent excipient wherein the several starting excipients are put into intimate contact generally via a specific process. Such multicomponent excipients are generally not a mere mixture as would be formed by plain mixing of the solid components together. Rather, usually the resulting excipient exhibits some degree of mutual agglomeration, impregnation, or coating of the excipients. In particular, celluloses have been studied in this regard.
For example, DE-C 3 506 276 discloses a combination of lactose monohydrate and powdered cellulose for direct tabletting. This composition is purported to have a high binding capacity.
DE-A 35 05 433 (U.S. Pat. No. 5,006,345) discloses an intimate mixture of lactose monohydrate, polyvinyl pyrrolidone and crosslinked, insoluble polyvinyl pyrrolidone. The mixture is generally formed by granulating the three components. The excipient is purported to have excellent flow properties and can provide, without further addition of a disintegrant, a rapidly disintegrating tablet.
U.S. Pat. No. 4,744,987 discloses a particulate co-processed microcrystalline cellulose and calcium carbonate composition wherein the respective components are present in a weight ratio of 75:25 to 35:65. The excipient has comparable tabletting properties as the cellulose itself, but at a lower cost.
U.S. Pat. No. 5,169,645 discloses directly compressible granules made by admixing flow improving additives into melted wax followed by cooling and granulation. The wax-containing granules are purported to have improved flow properties. The additives disclosed include, inter alia, a variety of polymers as well as finely divided silica, particulate sugars, and calcium gluconate, calcium phosphate, and calcium carbonate particles.
U.S. Pat. No. 5,585,115 discloses a pharmaceutical excipient based on a co-processed microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide particles, wherein the microcrystalline cellulose and silicon dioxide are in intimate association with each other. The intimate association is generally formed by spray drying an aqueous slurry of the two excipients. Such an excipient improves the compressibility of the cellulose.
Thus, in general there is a need for an excipient with good compressibility and binding properties. In particular, there is a need to improve the properties of calcium phosphate especially for use in solid dosage forms, including improving the abrasiveness, compatibility with pH-sensitive active agents, and/or release rate modifying effect.